Insecticide with juvenile hormone activity and a process of its preparation

ABSTRACT

HYDROCARBON CARBOXYLIC ACIDS AND ESTERS THEREOF HAVING A TERMINAL TERTIARY BUTYL GROUP USEFUL FOR CONTROL OF INSECTS.

United States Patent 6 3,707,491 IN SECTICIDE WITH JUVENILE HORMONEACTIVITY AND A PROCESS OF ITS PREPARATION Miroslav Romanuk, FrantisekSorm, and Karel Slama, Prague, Czechoslovakia, assignors toCeskosloveuska Akademie Ved, Prague, Czechoslovakia No Drawing. FiledMar. 19, 1970, Ser. No. 21,219 Claims priority, applicationCzechoslovakia, Apr. 9, 1969, 2,503/ 69 Int. Cl. A01n 9/24; C07c 57/02,69/52 US. Cl. 260-410.9 R 13 Claims ABSTRACT OF THE DISCLOSUREHydrocarbon carboxylic acids and esters thereof having a terminaltertiary butyl group useful for control of insects.

This invention relates to novel compounds with juvenile hormone activityfor the control of insects and a process of its preparation.

The juvenile hormone activity has been discovered in substancesoccurring in some plants, especially in the case of farnesol andtodomatsuic acid methyl ester (the socalled juvabione). A similaractivity has been found in lipidic insect extracts (probably due to thepresence of fatty acids) and in the so-called cecropia oil obtained fromthe butterfly Hyalophora cecropia. As discovered later, this oilcontained as the principal component the so-called cecropia juvenilehormone.

A number of synthetic compounds with juvenile hormone activity have beenrecently prepared, most of them being closely related to farnesoic acid.Particularly suitable are compounds containing a minimum of heteroatoms,especially halo atoms, in their molecule because of the lowered toxicitytowards warm-blooded animals. The last mentioned requirements aresuitably fulfilled by the present invention.

The present invention also relates to novel compositions with juvenilehormone activity, which compositions contain as active substance novelanalogues of farnesoic acid of the Formula I:

( uam CH3 CH:

OH: (I)

wherein, R designates hydrogen, lower alkyl, cycloalkyl or aralkyl; Rrepresents an alkyl group containing one to four carbon atoms, m is oneor two; and n is one or two. Hereinafter, each of R R m and n is asdefined heretofore, unless otherwise specified.

The term lower alkyl, as used herein, refers to a straight or branchedchain saturated aliphatic hydrocarbon group having a chain length of oneto six carbon atoms, such as methyl, ethyl, propyl, i-propyl, t-butyl,pentyl and n-hexyl. The term cycloalky as used herein, refers to acycloalkyl group having four to eight carbon atoms, such as cyclobutyl,cyclopentyl and cyclohexyl. The term aralky as used herein, refers to an3,707,491 Patented Dec. 26., 1972 CH3 CH;

and a,;8-alkylglutaric acid half-ester of the Formula III:

ornoooH H ornoooom thus forming an ester of the Formula IV:

COOCH:

CH; CH;

HI (IV) saponifying the latter, thus forming an acid of the Formula V:

CH; CH;

subjecting the latter acid to the Kolbe anodic synthesis either with5-alkoxycarbonyl-4-methyl-4-pentenoic acid of the Formula VI:

HOOC

R2 A om 0H (CH2)m \C/ C a CH;

and the subsequent vinyl hydroxy compounds.

(VII) The novel analogues of the Formula I are prepared according to theinvention by connecting three components with the use of the Kolbeanodic synthesis, namely,

Component A: represented by tert-butylacetic acid (3,3- dimethylbutyricacid) or tert-butylpropionic acid (4,4-dimethylvaleric acid);

Component B: represented by ,S-alkylglutaric acid halfester, the alkylgroup of which consists of one to four carbon atoms;

Component C: represented by alkoxycarbonyl 4- methyl-4-pentenoic acid ofthe Formula VI, or by B-hydroxy-B-methylglutaric acid half-ester, or3-methyl-3-hydroxy-S-hexenoic acid.

The above-mentioned sequence of reactions is preferably started with theuse of the Kolbe anodic synthesis to connect Component A with theComponent B under the formation of a monocarboxylic acid ester of theFormula IV.

In the case of fl-hydroxy-B-methylglutaric acid halfester as ComponentC, the resulting hydroxy ester is readily dehydrated to the requiredfarnesoic acid ester.

In the case of 3-methyl-3-hydroxy-5-hexenoic acid as Component C, theresulting intermediary vinyl hydroxy compound of the Formula VII is thensubjected to ozonization, dehydration and esterification.

In accordance with the present invention, there is provided a method forthe control of insects which comprises contacting the insects with acompound selected from those of Formula I above in an amount effectiveto inhibit the metamorphosis of said insects. To aid in achieving auniform distribution or application, it is advantageous to employ acomposition comprising an inert carrier and, as the essential activeingredient, a compound of Formula I. One method for the control ofinsects in accordance with the present invention is to apply thecomposition comprising an inert carrier and a compound of Formula I tothe locus of insect infestation, such as to the plant life on which theinsects live. These compositions can be either solid or liquid. Solidcompositions for treating insects can be prepared by incorporating theactive compound with an inert carrier, such as finely divided talc,silica, pyrophyllite or clay or granular inert carriers, such as thevermiculites. Liquid compositions can be prepared by mixing the activecompound with inert carriers, such as acetone, xylene, peanut oil,cottonseed oil, sesame oil and other vegetable oils and mineral oilsconventionally employed as carriers in insecticidal formulations forapplication by spraying. Emulsions containing the active ingredient canalso be used. Other ingredients can be present in the compositions ofthe present invention to aid in the effective application of the activeingredient, such as wetting agents, dispersing agents, insectattractants, and the like. The concentration of active ingredient of acompound of Formula I in the composition can vary greatly and willdepend on a variety of factors, such as the specific insect involved,degree of insect infestation, locus of insect infestation, environmentaland weather conditions and type of application device used, Generally,the composition will contain less than 95% by weight of the activeingredient and more frequently less than by weight. The compounds ofFormula I are useful insect control agents by virtue of their ability toinhibit the metamorphosis of the insect. The expression to inhibit themetamorphosis of said insect, as used herein, and in the appendedclaims, is used to describe the direct insecticidal effect of thecompounds of Formula I as well as the indirect insecticidal effect ofsaid compounds. In some cases the compounds have a direct insecticidaleffect in that the insect dies upon contact with a compound of FormulaI, particularly when the compound is applied at the egg stage and larvaestage of the insects life. In other cases, the compounds of the presentinvention have an indirect insecticidal effect in that upon contact witha compound of Formula I the egg stage, larvae stage or pupa stage, theinsect is unable to pass from one metamorphic stage to the next in anormal manner and eventually dies without reproducing.

The present invention will be further illustrated by the followingexamples although it is not limited thereto.

EXAMPLE 1 Preparation of methyl cis,trans 3,7,10,10-tetramethyl-2-undecenoate (a) Preparation of methyl3,6,6-trimethylheptanoate. Monomethyl fl-methylglutarate (3.50 g.) andtert-butylacetic acid (4.00 g.) are dissolved in methanol (10 ml.)containing sodium methoxide (60 mg). The resulting solution is subjectedto electrolysis according to Kolbe. Reaction conditions: reactionperiod, 8 hours; direct current, 6 volt, 0.35-0.30 amperes; reactiontemperature, 30- 35 C.; platinum electrodes, distance 2 millimeters; theinitial pH value, 6-7, the final pH value, 9-10. The electrolysis isinstantly interrupted as soon as the mixture shows an alkaline reaction.The reaction mixture is then evaporated under diminished pressure andthe residue is extracted with two 50 ml. portions of petroleum ether.The extract is concentrated and the concentrate is chromatographed on acolumn of a 50-fold amount (by weight) of silica gel. The elution isperformed with the use of a 10:1 petroleum etherether solvent mixture.Distillation of the principal chromatographic fraction affords 1.75 g.of methyl 3,6,6-trimethylheptanoate, a clear colorless liquid, B.P.70-73 C./ 12 mm. Hg. Infrared spectrum: the main maximum at 1725 cm.-

(b) Preparation of 3,6,6-trimethylheptanoic acid-The methyl ester of thepreceding paragraph (1.70 g.) is refluxed for three hours in a solutionof potassium hydroxide (5.0 g.) in 25% aqueous methanol (20 ml.). Thereaction mixture is evaporated under diminished pressure, the residuediluted with water (20 ml.) and washed with ether (20 ml.) to remove theneutral portions. The aqueous phase is acidified with 10% aqueoussulfuric acid to the pH value 3-4 and extracted with three 20 ml.portions of ether. The ethereal extracts are combined, washed with water(10 ml.), dried over anhydrous sodium sulfate and evaporated.Distillation of the residue alfords 1.45 g. of 3,6,6-trimethylheptanoicacid, B.P. 110l13 C./0.5 mm. Hg. Infrared spectrum: main maxima at 1412,1709 and 2400-3400 cm.- For C H O (172.3) calculated: 69.72% C, 11.70%H; Found: 69.36% C, 11.53% H.

(c) Preparation of methyl cis,trans 3,7,10,10tetramethylrZ-undecenOate.--The Kolbe anodic synthesis is performed inanalogy to paragraph (b) Reactants: 3,6,6- trimethylheptanoic acid (1.45g.), 5-rnethoxycarbonyl-4- methyl-4-pentenoic acid (2.10 g.), sodium (40mg.) and methanol (10 ml.). Conditions: six hours at 3540 C., 6 volt,0.20-0.30 ampere. The isolation and purification is performed on acolumn of silica gel also in analogy to paragraph (b). Distillation ofthe chromatographic ester fraction aifords 520mg. of methyl3,7,10,10-tetramethyl- 2-undecenoate, a clear colorless liquid, B.P.-102 C./ 0.5 mm. Hg. Infrared spectrum: main maxima at 1152, 1650 and1721 cm.- For C H O (254.4) calculated: 75.53% C, 11.89% H; Found:75.57% C, 11.83% H.

EXAMPLE 2 Preparation of ethyl cis,trans-3,7,10,10-tetramethyl-Z-undecenoate (a) 3,6,6-trimethylheptanoic acid is preparedin the same manner as given in Example 1(b).

(b) The Kolbe anodic synthesis, the isolation and the purification ofthe product is performed in analogy to Example 1(c). Reactants:3,6,6-trimethylheptanoic acid (1.50 g.),5-ethoxycarbonyl-4-methyl-4-pentenoic acid (2.35 g.), sodium (50 mg.)and methanol (10 ml.). Distillation of the appropriate chromatographic(silica gel) fraction affords '610 mg. of the title ethyl ester, a clearcolorless liquid, B.P. 117-119 C./0.5 mm. Hg. Infrared spectrum: mainspectra at 1150, 1650 and 1725 cm.- For C H O (268.4) calculated: 76.06%C, 12.02% H; Found: 76.26% C, 11.95% H.

EXAMPLE 3 Preparation of methyl cis,trans-3,10,lO-trimethyl-7-ethyl-2-undecenoate (a) Preparation of 6,6 dimethyl 3 ethylheptanoicacid.The title acid is prepared by the Kolbe anodic synthesis in analogyto Examples 1(a) and (b) and 2(a). Reactants: ,B-ethylglutaric acidmonomethyl ester (3.15 g.), tert-butylacetic acid (3.95 g.), sodium (35mg.) and methanol (10 ml.).The isolation procedure is also analogous tothat used in Examples 1 and 2. Yield, 1.66 g. of6,6-dimethyl-3-ethylheptanoic acid, a clear colorless liquid, B.P.122-125 C./ 0.5 mm. Hg. Infrared spectrum: main maxima at 1415, 1710 and2400-3400 cmr For C H O (186.3) calculated: 70.92% C, 11.90% H; Found:71.02% C, 11.74% H.

(b) Preparation of methyl cis,trans-3,10,IO-trimethyl-7-ethyl-2-undecenoate,.'Ihe Kolbe anodic synthesis and the isolationprocedure are performed in analogy to Example 1(c). Reactants:6,6-dimethyl-3-ethylheptanoic acid (1.50 g.),S-methoxycarbonyl-4-methyl-4-pentenoic acid (2.00 g.), sodium (50 mg.)and methanol (10 ml.). Chromatography and the subsequent distillationaffords 340 mg. of methyl 3,10,10-trimethyl-7-ethyl-2-undecenoate as aclear colorless liquid, B.P. ll2-l13 C./0.5 mm. Hg. Infrared spectrum:main maxima at 1150, 1650 and 1725 cm- For C H O (268.4) calculated:76.06% C, 12.02% H; Found: 75.89% C, 12.21% H.

The juvenile hormone activity was tested topically on freshly moultedlarvae of the last instar of the following Hemiptera: Pyrrhocorisapertus, Dysdercus cingulatus and Graphosoma italicum. In the case ofthe beetle Tenebrio molitor, the substance was injected into freshlymoulted pupae. The hormonal activity was evaluated according to thedegree of preservation of the larval (Hemiptera) or pupal (Tenebriomolitor) epidermal structures. Zero indicates the formation of perfectadults from larvae or pupae; activity 5 desginates formation of abnormalextra larvae or secondary pupae instead of an adult.

Activities 1-4 represent intermediary adultoid forms between larvae(pupae) and the adult insect according to the amount of the substanceused. The results are shown in the following table:

TABLE I Juvenile Hormone Activity for Methyl3,7,10,10-TetramethyI-Z-Undecanoate Dose in micrograms per specimenInsect 0. 01 O. 1 l. 0 10 100 Pyrrhocorz's apertus.-- 0 1 4 5 5Dysdercus cinguZatus 0 0 2 5 5 Graphosoma italicum. 0 0 0 3 5 Tenebriomolitor 1 2 3 4 5 EXAMPLE 4 Each of 3,7,10,10-tetramethylundec-Z-enoicacid and 3,10,10 trimethyl 7 ethylundec-Z-enoic acid is obtained fromthe corresponding methyl ester using the procedure of Example 1(b).

EXAMPLE 5 residue distilled in vacuo to yield benzyl3,7,10,10-tet'r'amethylundec-Z-enoate.

Other esters of Formula I can be prepared using this procedure bysubstituting the appropriate alcohol in place of benzyl alcohol, e.g.cyclopentyl alcohol, cyclohexyl alcohol, and the like.

EXAMPLE 6 Preparation of methylcis,trans-3,6,9,9-tetramethyl-2-decenoate (Formula I, m=n=1, R =R=methyl) (a) preparation of 2,2,5,S-tetramethyl-S-hydroxy-10- undecene.3,6,6-trimethylheptanoic acid (3.5 g.); Formula V, m: 1, R =methyl) and3-methyl-3-hydroxy-5- hexenoic acid (3.5 g.) are dissolved in methanol(10 ml.) containing sodium methoxide (60 mg.). The resulting solution issubjected to the Kolbe anodic synthesis (reaction period, ten hours);0.3-0.6 ampere at 24 volt; reaction temperature 35-45 C.; platinumelectrodes, dis tance 2 millimeter; initial pH value 6-7, the final pHvalue 9-10. The electrolysis is interrupted as soon as the reactionmixture begins to show the alkaline reaction. The methanol is thenevaporated under reduced pressure and the residue is chromatographed ona column of silica gel (100 parts by weight of silica gel per one partof the residue). Elution is effected with light petroleum-ether (7: 1).The eluate is evaporated and the residue distilled to afford 0.95 g. ofCompound VII (m=1, R =methyl), B.P. 105-108 C./ 0.6 torr. For C H O(220.4) calculated: 79.57% C, 13.36% H; Found:79.76% C, 13.49% H.Infrared spectrum: main maxima at 918, 1000, 1634, 3005 and 3070 cm.-(vinyl); 3610 cm.- (hydroxyl); 1367, 1393 cm.- (tert-butyl).

(b) Preparation of methyl 3-hydroxy-3,6,9,9-tetramethyldecanoate.-Amixture of ozone and oxygen (containing about 3% of 0 introduced slowlyinto a solution of the vinyl hydroxy compound of Part (a) in ethylacetate. The reaction is interrupted as soon as the mixture begins toassume a blue color (after about 20 minutes in this run). Water (15ml.), acetic acid (15 ml.) and hydrogen peroxide (3 ml.) are then added,the whole mixture refluxed for one hour, cooled to 20 C., diluted withadditional water (20 ml.) and extracted with five 15 ml. portions ofether. The ethereal extracts are combined, dried and evaporated underdiminished pressure. The crude residue is esterified by the addition ofethereal diazomethane, the ether is evaporated and the residue isdistilled under diminished pressure to afford 310 mg. (purity, of thehydroxy ester (methyl 3-hydroxy-3,6,9,9- tetramethyldecanoate), B.P. 105C./0.1 torr. Infrared spectrum: 1725 cm.- (ester), 3400 cm.- (hydroxyl).

(0) Preparation of methyl cis,trans-3,6,9,9-tetramethyl- 2-decenoate.Amixture of the hydroxy ester of Part (b) (180 mg.) and 98% formic acid(2.0 g.) is heated at -90 C. for two hours, allowed to stand at 20-25 C.for 15 hours and evaporated under diminished pressure. The residue isesterified by the addition of ethereal diazomethane, the ether isevaporated and the resulting residue is purified by columnchromatography on silica gel (100 parts by weight of silica gel per onepart of the residue). The elution is performed with lightpetroleum-ether (4: 1). The eluate is evaporated and the residue isdistilled under reduced pressure to afford 46 mg. of methyl 3,6,9,9-tetramethyl-Z-decenoate, B.P. -127 C./1 torr. For C H O (240.4)calculated: 74.95% C, 11.74% Found: 74.52% C, 11.76% H. Infraredspectrum: 1720, 1645 cm:- (unsaturated ester).

EXAMPLE 7 Preparation of ethyl cis,trans-3,6,9,9-tetramethyl-Z-decenoate (Formula I, m=n=l, R -=ethyl, R =methyl) (a) Preparation of2,2,5,8-tetramethyl-8-hydroxy-10- undecene. (The vinyl hydroxy CompoundVII, m=1,

R =methyl.)--The title compound is prepared according to Example 1, Part(a).

(b) Preparation of ethyl 3-hyd1'oxy-3,6,9,9-tetramethyldecanoate(IX).The title preparation is performed according to Example 1, Part (b)except for the esterifica tion of the crude residue which is effectedwith the use of ethereal diazoethane instead of ethereal diazomethane.Yield, 280 mg. of the hydroxy ester (IX), B.P. 116 C./ 0.1 torr (purity,about 80%). Infrared spectrum: 1725 and 3420 cmf (c) Preparation ofethyl cis,trans 3,6,9,9-tetramethyl- 2-decenoate.The title preparationis performed according to Example 1, Part except for the esterificationof the crude residue which is effected with the use of ethereal excessdiazoethane instead of ethereal diazomethane. Yield, 52 mg. of ethyl3,6,9,9-tetramethyl-2- decenoate, B.P. 137 C./1 torr. Infrared spectrum:1720 and 1640 cm."'

TABLE II Juvenile Hormone Activity Units of Methyl 8,6,9,9'Ietramethyl-2-D eeanoate Dose in pg. per specimen wherein, R ishydrogen, lower alkyl, cycloalkyl or aral'kyl; R is alkyl of one to fourcarbon atoms; m is one or two; and n is one or two.

2. A compound according to claim 1 wherein n is two. 3. A compoundaccording to claim 1 wherein each of n and m is two.

4. A compound according to claim 1 wherein R is lower alkyl.

5. A compound according to claim 1 wherein R is lower alkyl; R is methylor ethyl; and n is two.

6. A compound according to claim 5 wherein R is methyl or ethyl.

7. A compound according to claim 3 wherein R is methyl or ethyl.

8. A compound according to claim 7 wherein R is methyl.

9. A compound according to claim 1 wherein m is one; it is two; R ismethyl; and R is hydrogen, methyl or ethyl.

10. A compound according to claim 1 wherein m is one; It is one; R ismethyl; and R is hydrogen, methyl or ethyl.

11. A compound according to claim 1 wherein m is two; n is one; R ismethyl; and R is hydrogen, methyl or wherein, m is one or two and R isalkyl of one to four carbon atoms and the methyl ester thereof.

13. A compound according to claim 12 wherein R is methyl or ethyl.

References Cited UNITED STATES PATENTS 2/1969 Riiegg et a1 424333 5/1949Pavlic 260-540 OTHER REFERENCES Chemical Abstracts 52, 11783b (1958).

Chemical Abstracts 55, 384c385c (1961).

Chemical Abstracts, 3961b (1963).

Burrell et al.: J. Chem. Soc. No. 23, pp. 2144-54 (1966).

Fuson: Reactions of Organic Compounds John Wiley & Sons Inc., New York(1962), pp. 226-7 relied upon.

LEWIS GOTTS, Primary Examiner D. G. RIVERS, Assistant Examiner US. Cl.X.R.

2604l0, 410.5, 413, 488 F, 540 R, 632 R; 424-312, 318

